SUMMARY Depletion of circulating lymphocytes, hematologic toxicity, is a common accompaniment of multimodal cancer therapy. Lymphocytes are the most radiosensitive cells of the hematopoietic system. Radiation-induced depletion of circulating lymphocyte counts have a significant impact on overall survival outcomes for many solid cancers. This suggests that the immune system plays an important role in improving the efficacy of radiation therapy. Understanding the causes of radiotherapy induced hematologic toxicity will allow the development of novel strategies to predict, prevent and ameliorate this phenomenon and potentially improve patient outcome. The use of mice as model organisms for immunology research has led to significant advances in our understanding of the mechanisms governing human immune activation and regulation, as well as dysregulation. However, most mice studies use inbred strains with limited genetic diversity and do not reflect the diverse responses observed in humans. The Collaborative Cross (CC) was designed to overcome these limitations by modeling the genetic diversity found in the human population in a controlled and reproducible manner. Using the CC mouse resource, we have collected acute and persistent radiation sensitivity data in 983 CC mice covering 17 CC strains. Our preliminary QTL analysis identified several genetic loci associated with radiation sensitivity. One small, but highly significant QTL associated with acute radiation sensitivity of lymphocytes, B- and T-cells was located on distal chromosome 1 and encompassed only the Ush2A gene strongly suggesting that variations in this gene contribute to radiation sensitivity. Understanding the genes affecting immune system cells and treatment associated hematologic toxicity is the first step in developing novel therapies that are personalized according to an individual?s genetic make-up. In this proposal we will increase power of genetic detection of radiation sensitivity QTL, by expanding our existing radiation induced hematologic toxicity data set with an additional 13 CC strains. In aim 1 we will test the hypothesis that genetic variation and sex significantly influence radiation sensitivity of specific lymphocyte populations and blood parameters. In aim 2, we will test the role of Ush2a, identified in our preliminary QTL analysis in CC mice, in contributing to hematologic toxicity after radiation exposure. The identification of genetic markers associated with radiation sensitivity in our mouse cohort will result in a greater understanding of radiotherapy-induced lymphopenia, which may help design new therapeutic approaches to counter the effect. The Collaborative Cross immunophenotypic and radiation response data resource will become a valuable tool for the broad research community and will allow for association analysis among multiple complex phenotypes to address the contribution of the immune system in health and disease.